Innovative Therapies for Severe Asthma

More than 39.5 million people in the U.S. have been diagnosed with asthma, and about 3,400 deaths occur annually due to asthma complications.¹ Although the prevalence of atopy and asthma have increased over the past few decades in western countries, control and outcomes are improving.² Use of asthma protocols and early recognition by the primary care provider (PCP) are among the main reasons for trends toward decreased hospitalization and fewer asthma-related deaths.^3,4

In addition to the mainstay of treatments, including trigger avoidance, inhaled corticosteroids (ICS), and rescue bronchodilators, new therapies have been developed to supplement the treatment of severe persistent asthma, which constitutes about 5% to 10% of asthma cases. Severe asthma is defined as asthma that is unresponsive to baseline therapy.⁵

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Three sets of guidelines and recommendations exist to provide structure to asthma treatment decision making. The Expert Panel Report-3 (EPR-3) was created by the National Education and Prevention Program (NAEPP) and was last published in 2007. The NAEPP favors a stepwise approach, based on asthma severity and age group.³ The International European Respiratory Society (ERS) and American Thoracic Society (ATS) task force report was updated in 2014.⁵ The Global Initiative for Asthma (GINA) report, updated in 2016, now includes several of the advances in asthma care for those patients refractory to standard treatments.

Asthma Therapies

In this review, the authors cover therapies for severe asthma that are becoming more important for PCPs to consider, including exhaled nitric oxide (NO) levels, the use of tiotropium for asthma, the applicability of biologic agents, the use of allergen immunotherapy, and the usefulness of roflumilast. This review also covers antileukotriene therapy, bronchial thermoplasty, and a discussion of long-acting beta-agonist (LABA) therapy.

Fractional Exhaled Nitric Oxide

Nitric oxide is present in the exhaled breath and is elevated in those with eosinophilic asthma.⁶ The role of NO in asthma pathology is complex, involving proinflammatory qualities that contribute to airway hyperresponsiveness (AHR) and as a weak mediator of smooth muscle relaxation. In exhaled air, NO correlates with up-regulation of NO synthase (NOS), which occurs with inflammation, therefore, quantifying airway inflammation.^6-8

There has been some variability in the evidence supporting the use of fractional exhaled NO (FeNO) levels as a diagnostic tool. Some studies have suggested that FeNO is also elevated in other nonasthma conditions, such as eosinophilic bronchitis, atopy, and allergic rhinitis. Also, FeNO levels have been shown to be variably influenced by smoking, bronchoconstriction, and viral respiratory infections.⁹ However, FeNO levels > 50 ppb correlated most strongly with eosinophilic asthma and steroid responsiveness.⁹

Fractional exhaled NO tests now can be performed in the PCP office with NIOX VERO (Chicago, IL), a small, relatively inexpensive device. Although the 2016 GINA guidelines and the 2015 ERS/ATS guidelines do not offer specific recommendations for use and do not support withholding ICS based on FeNO test results, guidelines for FeNO use do exist. In 2011, ATS published a specific set of FeNO interpretive guidelines for office-based use.⁹ When performed in conjunction with standard testing, FeNO levels can provide valuable clinically relevant information, such as (1) detection of eosinophilic airway inflammation; (2) determining the likelihood of corticosteroid responsiveness; (3) monitoring of airway inflammation to determine the need for steroids; and (4) unmasking of otherwise unsuspected nonadherence to corticosteroid therapy (Table 1).

Tiotropium as an Adjunct Treatment

Tiotropium is a long-acting inhaled anticholinergic. A sentinel 1984 study by Gross and Skorodin demonstrated that parasympathetic activity is the dominant reversible component in patients with chronic obstructive pulmonary disease (COPD), including emphysema.¹⁰ In addition, all achievable bronchodilation was obtained with an inhaled anticholinergic compared with that of separate or simultaneous administration of adrenergics. Sympathetic neural pathways are sparse in human lungs and have their endings on the cells of the cholinergic postganglionic fibers, because sympathetic terminals on airway smooth muscle cells are rare or nonexistent.¹¹ Therefore, sympathetic modulation or activation of beta cells could change the parasympathetic tone.¹¹

The FDA approved the addition of tiotropium for treating asthma in September 2015 for patients aged ≥ 12 years. The use of tiotropium is supported by both the ERS/ASTS and GINA 2016 guidelines. The recommended and approved dose of tiotropium for asthma is 2.5 µg daily (the recommended dose for COPD treatment is 5 µg).¹² A recent phase 3 study compared 2.5 µg vs 5 µg dosing with ICS but no LABA in adolescents, noting significant improvement with the 2.5 µg dose.¹³ Adding tiotropium to ICS + LABA in patients with severe symptomatic asthma has been associated with positive results in initial studies by Kersjens and colleagues.¹⁴ Even as early as 2010, the use of tiotropium was shown to produce statistically significant improvement in morning peak expiratory flow (PEF), with a mean difference of 25.8 L/min (n = 210, P < .001).¹⁵

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Tiotropium also has been shown to provide a sustained reduction in lung hyperinflation for those with COPD, thus providing an improvement in exertional dyspnea and exercise tolerance. On day 42 of a randomized, double-blinded, placebo-controlled, parallel-group study of 187 patients, vital capacity and inspiratory capacity were noted to be increased with decreases in residual volume and functional residual capacity. Exercise endurance times increased by 105 ± 40 sec (21%).¹⁶ This effect has not been studied yet in a population of patients with asthma; however, the same principles may hold true.